Abstract
In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563. UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E.
Highlights
In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKDMBD among haemodialysis patients
These factors are frequently observed among patients with advanced chronic kidney disease (CKD)6,7, and vitamin D deficiency is highly prevalent in this population8–10
Vitamin D deficiency in CKD accelerates the development of mineral and bone disorder (MBD) and has been associated with adverse clinical outcomes such as a naemia11,12, cardiovascular events13, and mortality13,14
Summary
In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKDMBD among haemodialysis patients. Cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and reduces active vitamin D drugs. Vitamin D levels decrease with poor dietary intake and low UV-B e xposure, and inflammatory status (i.e., high interleukin-6 [IL-6]) inhibits the synthesis of vitamin D-binding protein (DBP) in the liver These factors are frequently observed among patients with advanced chronic kidney disease (CKD), and vitamin D deficiency is highly prevalent in this population. A short-term study of healthy subjects has shown that a single high-dose cholecalciferol supplementation markedly suppressed serum level of h epcidin, a type II acute phase protein that decreases iron availability via iron sequestration. It is important to develop an administration protocol that minimizes the pill burden and to identify which patients are more likely to benefit from vitamin D supplementation
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